Daniel Liebler
Faculty Member
Last active: 2/15/2016

Attenuation of the beta-catenin/TCF4 complex in colorectal cancer cells induces several growth-suppressive microRNAs that target cancer promoting genes.

Schepeler T, Holm A, Halvey P, Nordentoft I, Lamy P, Riising EM, Christensen LL, Thorsen K, Liebler DC, Helin K, ├śrntoft TF, Andersen CL
Oncogene. 2012 31 (22): 2750-60

PMID: 21963845 · DOI:10.1038/onc.2011.453

Aberrant activation of the Wnt signaling pathway is causally involved in the formation of most colorectal cancers (CRCs). Although detailed knowledge exists regarding Wnt-regulated protein-coding genes, much less is known about the possible involvement of non-coding RNAs. Here we used TaqMan Array MicroRNA Cards, capable of detecting 664 unique human microRNAs (miRNAs), to describe changes of the miRNA transcriptome following disruption of beta-catenin/TCF4 activity in DLD1 CRC cells. Most miRNAs appeared to respond independent of host gene regulation and proximal TCF4 chromatin occupancy as inferred from expression microarray and ChIP-chip data. A module of miRNAs induced by abrogated Wnt signaling in vitro was downregulated in two independent series of human primary CRCs (n=76) relative to normal adjacent mucosa (n=34). Several of these miRNAs (miR-145, miR-126, miR-30e-3p and miR-139-5p) markedly inhibited CRC cell growth in vitro when ectopically expressed. By using an integrative approach of proteomics and expression microarrays, we found numerous mRNAs and proteins to be affected by ectopic miR-30e-3p levels. This included HELZ and PIK3C2A that were directly repressed by several miRNA binding sites as confirmed by luciferase reporter assays in combination with mutational analyses. Finally, small interfering RNA-mediated downregulation of PIK3C2A, but not HELZ, was sufficient on its own to restrict CRC cell growth. Collectively, our study demonstrates that multiple miRNAs are upregulated as a consequence of forced attenuation of Wnt signaling in CRC cells, and some of these miRNAs inhibit cell growth with concomitant suppression of several growth-stimulatory cancer-related genes.

MeSH Terms (29)

Aged Aged, 80 and over Basic Helix-Loop-Helix Leucine Zipper Transcription Factors beta Catenin Cell Line, Tumor Cell Proliferation Chromatography, Liquid Colon Colorectal Neoplasms Female Gene Expression Profiling Genes, Dominant Humans Luciferases Male MicroRNAs Middle Aged Oligonucleotide Array Sequence Analysis Oncogenes Rectum Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger RNA, Small Interfering Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Transcription Factor 4 Transcription Factors Transcriptome Tumor Cells, Cultured Wnt Signaling Pathway

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